RT Journal Article
SR Electronic
T1 Inherited duplications of <em>PPP2R3B</em> promote naevi and melanoma via a novel <em>C21orf91</em>-driven proliferative phenotype
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 672576
DO 10.1101/672576
A1 Satyamaanasa Polubothu
A1 Lara Al-Olabi
A1 Daniël A Lionarons
A1 Mark Harland
A1 Anna C Thomas
A1 Stuart Horswell
A1 Lilian Hunt
A1 Nathan Wlodarchak
A1 Paula Aguilera
A1 Sarah Brand
A1 Dale Bryant
A1 Philip Beales
A1 Cristina Carrera
A1 Hui Chen
A1 Greg Elgar
A1 Catherine A Harwood
A1 Michael Howell
A1 Dagan Jenkins
A1 Lionel Larue
A1 Sam Loughlin
A1 Jeff MacDonald
A1 Josep Malvehy
A1 Sara Martin Barberan
A1 Vanessa Martins da Silva
A1 Miriam Molina
A1 Deborah Morrogh
A1 Dale Moulding
A1 Jérémie Nsengimana
A1 Alan Pittman
A1 Juan-Anton Puig-Butillé
A1 Kiran Parmar
A1 Neil J Sebire
A1 Stephen Scherer
A1 Paulina Stadnik
A1 Philip Stanier
A1 Gemma Tell
A1 Regula Waelchli
A1 Mehdi Zarrei
A1 Davide Zecchin
A1 Susana Puig
A1 Véronique Bataille
A1 Yongna Xing
A1 Eugene Healy
A1 Gudrun E Moore
A1 Wei-Li Di
A1 Julia Newton-Bishop
A1 Julian Downward
A1 Veronica A Kinsler
YR 2019
UL http://biorxiv.org/content/early/2019/06/15/672576.abstract
AB The majority of the heredity of melanoma remains unexplained, however inherited copy number changes have not yet been systematically studied. The genetic environment is highly relevant to treatment stratification, and new gene discovery is therefore desirable. Using an unbiased whole genome screening approach for copy number we identify here a novel melanoma predisposing factor, familial duplications of gene PPP2R3B, encoding a regulatory unit of critical phosphatase PP2A. Significant correlation between expression of PPP2R3B in tumour tissue and survival in a large melanoma cohort was confirmed, and associated with a non-immunological expression profile. Mechanistically, construction and extensive characterization of a stable, inducible cellular model for PPP2R3B overexpression revealed induction of pigment cell switching towards proliferation and away from migration. Importantly, this was independent of the known microphthalmia-associated transcription factor (MITF)-controlled pigment cell phenotype switch, and was instead driven by uncharacterised gene C21orf91. Bioinformatic studies point to C21orf91as a novel target of MITF, and therefore a potential hub in the control of phenotype switching in melanoma. This study identifies novel germline copy number variants in PPP2R3B predisposing to melanocytic neoplasia, and uncovers a new potential therapeutic target C21orf91 in the control of pigment cell proliferation.